A major problem for the use of monoclonal antibodies (MoAb) in the diagnosis and treatment of cancer has been the variability in binding of MoAb to tumor cells. Both the antigenic heterogeneous nature of neoplasms and host organ factors contribute to this variability. One potential approach to circumvent this heterogeneity is the concomitant use of multiple MoAb, each recognizing a different epitope on target cells. Another approach is the administration of MoAB a long with biological agents, e.g., IFN-alpha that can increase expression cell surface moieties on tumor cells. Most of the data on these approaches have been derived from in vitro conditions and in vivo in nude mice. Because the organ environment can influence the extent of tumor vascularization, we shall also study the localization of several 125I-labeled MoAbs (specific and nonspecific, alone or in combination) into human melanoma tumor lesion growing at primary sites (skin) and at metastatic sites (lung,liver). The ability of these MoAbs (alone or in combination) to detect the presence of occult metastases will also be determined. The effects of both recombinant alpha interferon (rIFN-alpha-a) and recombinant gamma interferon (rIFN-gamma) as well as other differentiating agents on modulation of suface antigen expression and subsequent binding of radiolabeled MoAb and then be tested in vitro using direct radioimmunoassay and flow cytometry techniques and then in vivo in nude mice with human melanoma deposits in primary and metastatic sites. The data derived from these studies should have direct bearing on clinical use of MoAb in human patients.